Kidney stone disease is a substantial health problem associated with significant pain, suffering, and economic costs. By the age of 70, 5% to 15% of the population will have a symptomatic episode of a stone and at least 50% of these individuals will have recurrent stone disease. Idiopathic calcium oxalate stone disease accounts for the majority of stone forming patients. It is generally accepted that idiopathic stone patients do not have dramatic anatomic, metabolic, or physiologic abnormalities. Idiopathic CaOx stone disease appears to require both supersaturation of the urine with respect to calcium and oxalate and tissue injury in the late collecting duct for crystals to attach, initiating stone development. The injury site appears to be highly localized to the site of the stone. Animal studies to date have used dramatic hyperoxaluric conditions that may have limited our ability to see the early events resulting from chronic mild hyperoxaluria as seen in idiopathic CaOx stone patients. No animal studies to date have explored the potential impact of chronic exposure of low levels of oxalate as might be seen in the idiopathic stone patients. This grant focuses on the attachment of urinary crystals to injured kidney papillary tip urothelium and the conditions and events that allow for crystal attachment. We will study long-term exposure of low to mild oxalate levels that might be associated with papillary tubular or vascular injury. The hypothesis to be tested is that CaOx crystal attachment to late collecting duct urothelium is dependent on localized injury that may originate in either the late collecting duct or in the vasculature intimately associated with the tubule crystal attachment site. We also hypothesize that chronic low levels of oxalate exposure as may be seen in idiopathic calcium oxalate stone patients may be sufficient to induce this injury. This grant proposal contains three Specific Aims to test this hypothesis. Specific Aim I: To determine if chronic exposure to oxalate levels insufficient for widespread CaOx crystal formation leads to the disruption of normal tubule physiology and the initiation of injury associated with effective urothelial crystal attachment and stone formation. Specific Aim II: To determine if tubule injury necessary for effective crystal attachment stems from oxalate-induced changes in the associated vasculature. Specific Aim III: To determine if oxalate-associated injury leading to effective CaOx crystal attachment and stone formation is exacerbated by the presence of other vascular and tubule injuries such as that associated with hypertension.